Sleep, or the natural periodic suspension of consciousness during which the powers of the body and mind are restored, is an essential component of human life. It has long been clear that sleep is crucial for sustaining normal function and the mental and physical well-being of all animals. Common wisdom, partially based on everyday human experiences, and shared by members the scientific and medical communities and laypersons alike, is that sleep is an opportunity for the human body to get much needed repair. The types of repair during sleep include physical repair, such as the repair of torn muscles, organ cleansing, etc., and psychological repair, such as the laying down of memories, working though anxiety, etc.
It is well known that sleep occurs naturally in response to the duration of wakefulness and is regulated by a number of brain processes. The longer a person is awake, the stronger their desire to sleep. However, it is the brain that controls the timing of sleep and wakefulness during the day-night cycle through a physiological mechanism generally referred to as a circadian, or biological, clock (see, for example, “Let Sleep Work for You”, National Sleep Foundation, Washington, D.C. (2003)). Daily biological rhythms, including sleep-wake cycles, are generally referred to as circadian rhythms. Circadian clocks are known to exist in mammals, plants, fungi, insects, etc., and run on approximately a 24 hour cycle that corresponds to the day-night cycle of the Earth. The molecular mechanisms underlying biological clocks are best understood in Drosophila, a fruit fly, and involve a light-sensitive protein cryptochrome, and a complex system of proteins whose transcription, translation, and degradation are intricately regulated in response to daylight or the absence of daylight.
In mammals, the process is less well understood than in other organisms. However, it has been established that the master clock mechanism in mammals is associated with the suprachiasmatic nucleus (SCN), a distinct group of around 10,000 cells located in the hypothalamus of the brain. Peripheral clocks, located in every cell, are regulated by the SCN. Light receptors in the retina are connected to the SCN through a pathway called the retinohypothalamic tract. Recent studies suggest that the light receptors receive signals from the retinal cells (rods and cones) and pass the signals on either to vision areas of the brain or directly to SCN. The SCN then sends the signals to clocks in the rest of the body. Both cryptochrome and melanopsin proteins have been suggested as the candidate light sensitive proteins in mammals. However, the circadian pathways of a mammalian brain, including that of Homo sapiens, remain to be deconvoluted (Barinaga, “How the Brain's Clock Gets Daily Enlightenment” Science 295:955 (2002)).
Thus, in spite of a familial and persuasive presence of sleep in human life and an extensive body of sleep research, the details of sleep regulating machinery remain unknown at this time. Interestingly, the exact function of sleep is also considered to be unknown, even though sleep has been implicated, for example, in the plastic cerebral changes that underline learning and memory (Maquest, “The Role of Sleep in Learning and Memory” Science 294:1048-1052 (2001)). Also, the so-called “sleep architecture”, or predictable patterns of brain activity alternating approximately every 90 minutes between REM (rapid-eye movement) and NREM (non-rapid eye movement) sleep throughout a typical eight hour period are well known, as is the fact that both REM and NREM states are important for experiencing quality sleep.
While the exact mechanisms regulating sleep in humans may not be revealed for many years, methods and tactics for treating sleep disturbances and problems must be addressed on a day-to-day basis for a significant number of individuals who require continuous and restorative sleep in order to feel refreshed and alert during their wakeful periods of time.
Sleep disturbances are common in humans and lead to a variety of physical and mental problems in a significant portion of the population. The 2002 National Sleep Foundation (NSF) “Sleep in America” poll revealed that 74 percent of American adults experience a sleeping problem a few nights a week or more. According to some sources, 32 percent of Persian Gulf War veterans listed sleep disturbance as one of their top seven maladies after returning from the Persian Gulf. Sleep disruptions lead, for example, to pain, fatigue, memory and thinking difficulties, difficulty maintaining alertness, lack of energy, irritability and, a generally impaired mood with difficulty handling stress. Lack of sleep also puts one at risk for injury and accidents, such as those caused by falling asleep while operating machinery, with approximately 100,000 sleep-related vehicle crashes resulting in approximately 1,500 deaths each year. In addition, disrupted sleep leads to poor performance at work, difficulty getting along with others, problems completing a task, poor concentration, inability to make decisions and an increase in the frequency of unsafe actions. Insufficient sleep may also make it difficult to exercise and can reduce the benefit of hormones released during sleep. In addition, inadequate amounts of sleep suppress the immune system, thereby increasing susceptibility to disease and, according to some research, increase the risk of developing obesity and diabetes and impact aging (“Let Sleep Work for You”, National Sleep Foundation, Washington, D.C. (2003)). Productivity lost due to sleepiness has been estimated to cost the national economy as much as 100 billion annually (“When You Cannot Sleep. ABCs of ZZZs, National Sleep Foundation, Washington, D.C. (2003)).
It is commonly known and reported by authoritative sources, such as those published by the National Sleep Foundation, that causes of sleep disruptions are multiple and varied (see, for example, When You Cannot Sleep. ABCs of ZZZs, National Sleep Foundation, Washington, D.C. (2003), excerpts of which are quoted in this section). One group of causes is psychological factors, with stress being the primary cause of short-term sleeping difficulties. Common triggers include school- or job-related pressures, a family or marriage problem, and a serious illness or death in the family. While most sleep problems disappear when the stressful situation is over, if short-term sleep problems are not managed properly, they can persist long after the original stress has passed. Another common group of causes are lifestyle stressors, including consumption of alcohol or caffeine and other stimulants, exercising close to bedtime, following an irregular morning and nighttime schedule, and working or doing other mentally intense activities right before or after getting into bed.
A further source of sleep disturbances includes disruptions of the normal day-night cycle, such as shift work and jet lag, which often cause disturbances in the circadian rhythms. Approximately 20 percent of employees in the United States are shift workers. They are two to five times more likely than employees with regular, daytime hours to fall asleep on the job. The term “jet lag” is commonly used to refer to an inability to sleep caused by travel across several time zones. Among other sleep disruptors are environmental interferences, such as a room that is too hot, cold, noisy or brightly lit, interruptions from children or other family members, or excessive noise. Environmental factors are often particularly troublesome for persons involved in active military actions or hospital patients.
A number of physical problems also interfere with the ability to fall asleep or stay asleep. For example, arthritis and other conditions that cause pain, backache, or discomfort can make sleeping difficult. In post-surgical recovery, sleep disruptions due to pain and discomfort present a particular problem because interrupted sleep is believed to interfere with healing. Disorders that cause involuntary limb movements during sleep, such as Restless Legs Syndrome, break up normal sleep pattern and are also likely to make sleep less refreshing, resulting in daytime sleepiness. For women, pregnancy and hormonal shifts including those that cause premenstrual syndrome (PMS) or menopause and its accompanying hot flashes can intrude on sleep. In addition, certain medications such as decongestants, steroids and some medicines for high blood pressure, asthma, or depression can cause sleeping difficulties as an adverse side effect.
According to the National Sleep Foundation certain individuals are particularly vulnerable to disrupted sleep, including, but not limited to, students, shift workers, travelers, and persons suffering from acute stress, depression, or chronic pain (“When You Cannot Sleep. ABCs of ZZZs, National Sleep Foundation, Washington, D.C. (2003)). Employees working long hours or multiple jobs may find their sleep less refreshing. Teenagers can have difficulty falling asleep until late at night and some awaken early the following morning. Many young adults keep relatively irregular hours and, as a group, report higher rates of dissatisfaction with the sleep obtained. Obesity and excessive body weight also increase the risk of insomnia.
Older adults also have frequent difficulty with sleep. With advanced age, the total amount of sleep needed in a 24 hour period is not reduced, but common sleep disruptors, such as impaired health, pain and the increased use of medications are prevalent. In older adults, sleep-wake cycle disturbances and circadian-based sleep imbalances are also widespread. Reduced endogenous melatonin production that is secondary to the process of aging can cause these sleep disruptions.
In view of the foregoing, it is evident that sleep disturbances are a prevalent and serious problem in the human population. Sleep disturbances are currently counteracted using a variety of resources and approaches, including lifestyle modifications, behavioral treatments, medications and nutritional supplements. Prescription drug medications that promote sleep include hypnotics, anti-depressants, and anti-anxiety drugs. All of the available prescription medications can cause serious side effects such as, for example, rebound insomnia, which occurs when a person stops taking a prescribed medication and experiences one or two nights of insomnia that are worse than those experienced before treatment. Another side effect to medical treatment with is the development of an addiction to the medication. The beneficial effects of a drug prescribed for insomnia may not subside when desired resulting in day-time sleepiness, impairment of concentration, and excessive sedation. Also, certain anti-insomnia medications cannot be combined with other sedatives, such as alcohol, and should be avoided by people with certain medical conditions. Sleep aids that are available without a prescription, or “over-the-counter” (OTC) sleep promoters, such as antihistamines and pain-relievers, promote sleep by virtue of their sedative properties, but are prone to many of the same undesirable side effects as prescription sleep aids.
Among the currently available selection of non-prescription sleep aids are certain nutritional supplements. When administered, usually by oral ingestion, these nutritional supplements provide an increased amount of a substance either occurring naturally in a human body or commonly contained in a food consumed by humans. One such nutritional supplement is melatonin, which is the principal product of the mammalian pineal gland. Melatonin acts as an internal representative of nighttime. Production is confined to the hours of darkness both by an appropriately phased circadian rhythm of pineal stimulation and by an extreme sensitivity of pineal melatonin synthesis to inhibition by light (J. Arendt, MELATONIN AND THE MAMMALIAN PINEAL GLAND [Chapman & Hall, Cambridge, 1995]). The production of melatonin is induced by the perception of darkness as transmitted from the eyes to the pineal gland between the two hemispheres of the brain. The pineal gland of a normal person produces approximately 500 mcg (micrograms) of melatonin daily. However, starting at age 12, or even earlier, production of this key hormone goes into steady decline. In an octogenarian the amount of melatonin produced is quite nominal. Reduced endogenous melatonin production can cause sleep-wake cycle disturbances and circadian-based sleep imbalances.
Melatonin is currently available commercially as a treatment for insomnia. In the United States, it is available without a prescription, in sublingual and tablet form. Unfortunately, the results of various studies conducted to ascertain the sleep-promoting properties of the currently available melatonin compositions have been inconsistent and many lack objective criteria for ascertaining sleep improvements. Studies that have contained objective criteria failed to show that melatonin is demonstrably beneficial for promoting sleep.
In view of the foregoing, there is a clear, unrealized need for sleep regulating treatments, specifically effective treatments that promote healthful sleep and counteract sleep disturbances without causing adverse side effects such as rebound insomnia, excessive sedation, inappropriate sleepiness, loss of concentration, or formation of habit. Particularly, compositions are needed that reliably, consistently, and beneficially regulate sleep or circadian rhythms, or both, in an individual, such as a human or an animal. Compositions that regulate sleep in patients with sleep-wake cycle disturbances and circadian rhythm imbalances are desired. Compositions that induce sleep, as well as those that help a patient remain asleep are needed. Older adults are in particular need of such compositions. Also, older adults are in need of the compositions that would help counteract reduced endogenous melatonin production associated with aging.